Payers Have Biologic Alternative for Patients With Moderate to Severe Rheumatoid Arthritis Who Do Not Respond to Other DMARD Therapies

Abstract

Earlier biologic therapies for rheumatoid arthritis represented a breakthrough in treatment of the disease, but there are still some patients who do not respond adequately to them. The market entry of abatacept, which allows for consistent dosing and predictable drug-acquisition costs, presents patients, physicians, and third-party payers with an effective alternative – the first therapy proven to be effective in patients with inadequate response to DMARDs such as methotrexate or anti-TNF-alpha therapies.

Biomedical advances have helped patients live more satisfying lives with conditions for which until recently few, if any, viable therapies existed. Rheumatoid arthritis (RA), which affects approximately 2.1 million Americans,1 is one such disease. An autoimmune disease that causes pain, swelling, stiffness, and erosion of synovial joints, RA was — until the advent of disease-modifying anti-rheumatic drug (DMARD) therapies — a condition for which medicine had little to offer beyond analgesics and anti-inflammatory drugs.2

DMARDs are drugs with the ability to reduce both inflammation and the progression of joint damage caused by RA.3,4 The emergence in the last decade of biologic DMARDs — which for the first time used a rational approach to target specific pathways in the disease process — proved to be an important therapeutic advance. Unfortunately, there are still some patients who do not respond to these initial biologic agents.2

Subsequently, biologic DMARDs have emerged that demonstrate therapeutic effectiveness for many RA patients who did not respond adequately to initial biologic therapy. In the past 12 months, the U.S. Food and Drug Administration has approved two first-in-class drugs with unique mechanisms of action (MOA). Orencia^® (abatacept) is a selective costimulation modulator that inhibits full T-cell activation.5 Rituxan^® (rituximab), previously approved for the treatment of non-Hodgkin’s Lymphoma, binds to CD20-positive B cells, leading to their depletion.6 Only abatacept is specifically indicated for patients with inadequate response to both DMARDs, such as methotrexate, or the newer biologic tumor necrosis factor-α (TNF-α) inhibitors.^*

BIOLOGICS NOT ALL ALIKE

Three of the first four biologic agents approved to treat RA — Enbrel^® (etanercept), Remicade^® (infliximab), and Humira^® (adalimumab) — work similarly to inhibit TNF-α.7,8,9 The fourth, Kineret^® (anakinra), blocks another cytokine, interleukin-1.10

The TNF-α antagonists and anakinra impacted the lives of many people living with the burden of RA, whose symptoms frequently abated and whose disease sometimes went into remission. As with many medications, however, these therapies are not effective for everyone. Patients, who for a variety of clinical reasons do not achieve an adequate response, may be candidates for treatment with abatacept. Failure on prior drugs has no bearing on whether a particular patient will do well on a subsequent medication utilizing a different MOA.

Abatacept, the first selective co-stimulation modulator to receive FDA approval, inhibits one of two signals from antigen-presenting cells (APCs) that are required for full T-cell activation. Full T-cell activation begins the cascade that leads to the production of many inflammation-inducing cytokines. Anti-TNF-α agents inhibit cytokines, but act later in the inflammation process.

CLINICAL STUDIES OF ABATACEPT

Various randomized, double-blind, placebo-controlled clinical trials have demonstrated abatacept’s efficacy and safety. In the phase III Abatacept in Inadequate responders to Methotrexate (AIM) trial, reported in the June 2006 Annals of Internal Medicine, abatacept was studied with patients who had an inadequate response to methotrexate. All patients, including those receiving placebo, continued on their stable dose of methotrexate and were followed for 1 year. The study authors observed improved ACR response rates through 1 year among patients given abatacept compared with placebo. Statistically significant improvements in pain and physical function were observed, in some patients within 15 days. One-year radiographic data also indicated lessened progression of structural joint damage.11

Similarly, when abatacept was used in patients with an inadequate response to prior therapy with etanercept and infliximab in the 6-month Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN) phase III study, published in the New England Journal of Medicine, “Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-α therapy.”12^* Despite participants having had RA for an average of 12 years, primary and secondary outcomes^† were achieved at 6 months in the abatacept group as compared with the placebo group. “Clinical improvements in ACR20 and [Health Assessment Questionnaire] HAQ responses were seen at day 15, and the rates increased over the 6-month study period,” the authors noted. Abatacept therapy also demonstrated significant improvement in physical function.

Abatacept also is approved for use as monotherapy. In an earlier, phase IIb, 3-month study of RA patients who had failed at least one nonbiologic DMARD or etanercept, ACR20, -50 and -70 responses were significantly better in patients who were administered abatacept alone compared with placebo.5

Results of these trials are shown in Table 1 on page 26.

TABLE 1.

ACR responses in Orencia^® (abatacept) placebo-controlled trials

Clinical study	Inadequate response to DMARDs (3-month study)		Inadequate response to methotrexate (AIM study, 12 months)		Inadequate response to anti-TNF-α (ATTAIN study, 6 months)
	Abatacept a n=32)	Placebo (n=32)	Abatacept b +MTX (n=424)	Placebo +MTX (n=214)	Abatacept b +DMARD (n=256)	Placebo +DMARD (n=133)
Response rate (% of subjects) (P values vs. placebo)
ACR 20
Month 3	53	31	62‡	37	46‡	18
Month 6	NA	NA	68‡	40	50‡	20
Month 12	NA	NA	73‡	40	NA	NA
ACR 50
Month 3	16	6	32‡	8	18†	6
Month 6	NA	NA	40‡	17	20‡	4
Month 12	NA	NA	48‡	18	NA	NA
ACR 70
Month 3	6	0	13‡	3	6*	1
Month 6	NA	NA	20‡	7	10†	2
Month 12	NA	NA	29‡	6	NA	NA

^*P<0.05, Orencia vs. placebo.

^†P<0.01, Orencia vs. placebo.

^‡P<0.001, Orencia vs. placebo.

^a10 mg/kg.

^bDose based on weight range (see full prescribing information).

DMARD=disease-modifying antirheumatic drug, MTX=methotrexate.

More recently, a review of the long-term extension of the AIM trial results was presented at the 2006 European League Against Rheumatism (EULAR) conference. In RA patients treated with abatacept plus methotrexate for 2 years, 80 percent achieved ACR20 responses at month 24, while ACR50 and -70 responses were 56 percent and 34 percent respectively.13 Jean-Claude Becker, MD, director of clinical research for Bristol-Myers Squibb and a co-investigator of the study, says the 2-year data are particularly impressive, because they suggest sustained effectiveness. “It’s a very solid response,” he says. Prolonged efficacy is an important trait in RA therapy, he notes, adding that “When you target the mechanism of inflammation, you may have a very sustained effect.”

Studies also show improvement in physical function, as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). In two separate studies of patients with an inadequate response to methotrexate, those receiving abatacept plus methotrexate demonstrated greater improvement from baseline than subjects who received a placebo plus methotrexate (Table 2, page 26). During an open-label extension of a phase IIb study of patients with inadequate response to methotrexate, improvement in physical function was maintained for up to 3 years.

TABLE 2.

Mean improvements from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)

	Inadequate response to methotrexate
	Study II		AIM study
	Abatacept a +MTX (n=115)	Placebo +MTX (n=119)	Abatacept b +MTX (n=422)	Placebo +MTX (n=212)
Baseline	0.98c	0.97c	1.69d	1.69d
Mean improvement, year 1	0.40c*	0.15c	0.66d*	0.37d

^*P<0.001, Orencia vs. placebo.

^a10 mg/kg.

^bDosing based on weight range (see full prescribing information).

^cModified Health Assessment Questionnaire: 0=best, 3=worst; 8 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

^dHealth Assessment Questionnaire: 0=best, 3=worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

MTX=methotrexate.

These studies present third-party payers with evidence of effectiveness of abatacept, and give physicians and patients a greater number of clinically proven alternatives than in recent years. “Patients have an opportunity to receive a treatment that targets an important mechanism of action,” Becker says. Response to abatacept, he says, was achieved “in patients who had failed either a TNF-α inhibitor or other DMARDs and with long duration of disease. These patients still had an ACR20 response of at least 30 percent above the placebo response. You will never have 100 percent response for any mechanism. This level of response is a big achievement.”

A DIFFERENT MOA

There are multiple existing co-stimulatory pathways involved in T-cell activation. These pathways serve either to upregulate or down-regulate T-cell activity. By selectively targeting the most well-characterized costimulatory pathway in RA immunopathology, CD80/86-CD28, with Orencia (abatacept), T-cell activation is not expected to be completely blocked, while other pathways that modulate T-cell activation may continue to function.14,15,16

The unique upstream action of Orencia at the T-cell level (Figure) leads to selective inhibition of T-cell activation as well as downstream activation of effector cells and the subsequent release of the cytokines and inflammatory mediators that cause the inflammation and destruction that are characteristic of RA.17,18

FIGURE.

Orencia^® (abatacept) is a first-in-class selective costimulation modulator with a unique mechanism of action that is fundamentally different than any other therapy for rheumatoid arthritis.

WARNINGS AND PRECAUTIONS

Concurrent therapy with abatacept and a biologic DMARD is not recommended. In controlled clinical trials, patients receiving concomitant abatacept and TNF-α antagonist therapy experienced more infections (63 percent) and serious infections (4.4 percent) compared with patients treated only with TNF-α antagonists (43 percent and 0.8 percent, respectively), without an important enhancement of efficacy.

Precautions include infusion-related and hypersensitivity reactions (including anaphylaxis), malignancies, worsening of chronic obstructive pulmonary disease (COPD) symptoms in COPD patients, concurrent use with live vaccines, and immunosuppression. The most serious adverse reactions are serious infections and malignancies. The most common adverse reactions are headache, upper respiratory tract infection, nasopharyngitis, and nausea.^*

PREDICTABLE DOSING

For third-party payers, predictable drug-acquisition prices on a per-patient basis are important. One issue within this context is that of potential dose escalation. With some medications, rheumatologists prefer dose escalation, because it permits greater flexibility in fine-tuning treatment to elicit a therapeutic response. For third-party payers, though, drug-acquisition costs could be less predictable when there is dose flexibility.

Dose escalation is “insidious,” Neil B. Minkoff, MD, medical director for network services and pharmacy at Massachusetts-based Harvard Pilgrim Health Care, says in an interview with Biotechnology Healthcare. “After adding an agent to a formulary, you start seeing significantly higher drug-acquisition costs than expected, because of the higher doses than were used in forecasting. It becomes very difficult for a plan, then, to say that only low doses of a medication are covered.”

Abatacept offers consistent weight-based dosing at fixed intervals and is administered monthly in a medical setting via 30-minute intravenous infusions at a dosage of approximately 10 mg per kilogram of body weight.^* Patients weighing <60 kg receive 500 mg; 60–100 kg receive 750 mg; and >100 kg receive 1 g. This corresponds to 2, 3, or 4 vials, respectively, used in their entirety with no waste.

Becker notes that the clinical studies for abatacept all used consistent dosages. “We have not seen dose escalation to achieve response. There are no data to suggest that we need to adjust the dosage. Patients are doing well at 6 months, 1 year, and 3 years out.”

CONCLUSION

As the only biologic DMARD approved for adult patients with moderate to severe RA who do not respond adequately to either methotrexate or TNF-α inhibitors, abatacept has been shown to be an effective biologic alternative. For third-party payers managing the RA category, consistent dosing offers predictable drug-acquisition costs. This is an important consideration in a complex market for biologic RA therapies.